Entry of oximes into the brain: A review

D. E. Lorke, H. Kalász, G. A. Petroianu, K. Tekes

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow. since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.

Original languageEnglish
Pages (from-to)743-753
Number of pages11
JournalCurrent Medicinal Chemistry
Volume15
Issue number8
DOIs
Publication statusPublished - Apr 2008

Fingerprint

Oximes
Cerebrospinal fluid
Brain
Cerebrospinal Fluid
Blood
Acetylcholinesterase
Blood-Brain Barrier
Carrier transport
Tight Junctions
Endothelial cells
Neurology
Epithelium
Central Nervous System
Endothelial Cells
Organophosphate Poisoning
Transcytosis
Choroid Plexus
Fluids
Organophosphates
Poisons

Keywords

  • Blood-brain barrier
  • Cerebrospinal fluid
  • Organophosphates
  • Oxime
  • Paraoxon
  • Pralidoxime

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

Entry of oximes into the brain : A review. / Lorke, D. E.; Kalász, H.; Petroianu, G. A.; Tekes, K.

In: Current Medicinal Chemistry, Vol. 15, No. 8, 04.2008, p. 743-753.

Research output: Contribution to journalArticle

Lorke, D. E. ; Kalász, H. ; Petroianu, G. A. ; Tekes, K. / Entry of oximes into the brain : A review. In: Current Medicinal Chemistry. 2008 ; Vol. 15, No. 8. pp. 743-753.
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